PROJECT SUMMARY The ongoing COVID-19 pandemic is an urgent public health crisis with few if any rapid and practical solutions. From the time that severe acute respiratory syndrome (SARS) coronavirus 2, SARS-CoV-2, was first reported there have been approximately 2.7 million cases worldwide, 900,000 of which occurred in the United States; resulting in nearly 50,000 American deaths to date. Given the seriousness and time-sensitive nature of this highly contagious virus, the medical and scientific communities must work quickly and efficiently to find a feasible way to address this global emergency. While SARS-CoV-2-infected patients most commonly present with fever, tiredness and dry cough; a significant subset of these patients present with gastrointestinal (GI) issues such as diarrhea, alluding to the potentially understated role of SARS-CoV-2 in the intestine. A recent study found that fecal viral shedding can continue as long as 5 weeks after the last detection of SARS-CoV-2 RNA in respiratory samples, suggesting that the GI tract serves as a viral reservoir and allows for prolonged COVID-19 infection and transmission. Given that SARS-CoV-2 is so highly contagious, can be easily spread by both respiratory droplets and fecal- oral route, and can be passed on by asymptomatic carriers, limiting its transmission is paramount to public health. There is a critical need to develop practical COVID-19 intervention strategies to treat SARS-CoV-2 infection and to prevent person-to-person transmission. There are no current proven treatments for COVID-19, and significant efforts are going toward developing novel therapeutics that have not been assessed for safety in humans. Repurposing reliable and effective drugs for COVID-19 therapy is not only a safer strategy, but will also allow for more rapid introduction into clinical practice. For this reason, we propose to use the widely used antihelmintic drug, Niclosamide (NIC), for treatment of COVID-19. FDA-approved NIC, is an oral medication used to treat tapeworm infestations, which is on the World Health Organization (WHO) List of Essential Medicines. NIC was found to inhibit SARS- CoV-2 in in vitro studies, and was also found to inhibit similarly structured RNA viruses both in vitro and in vivo. Its mechanism of action in this capacity is to increase the pH within acidic endosomes of host cells, thereby inhibiting virus entry and release. Importantly, NIC has also demonstrated anti-inflammatory activity, and has been shown to function as a bronchodilator in animal studies. Our overall goal is to determine the potential of NIC as both a treatment early in the course of COVID- 19 infection as well as a prophylactic measure to prevent spread of SARS-CoV-2 virus. As such, we propose to conduct a randomized, double-blind controlled clinical trial to evaluate the efficacy of NIC in shortening contagious period of COVID-19 as determined by time to viral clearance from both respiratory and fecal samples, as well as its ability to mitigate clinical outcomes of the disease.